PROJECT SUMMARY Psychostimulants used to treat attention deficit hyperactivity disorder (ADHD) are the second most prescribed medication class for long-term use in children and adolescents. These medications have long been known to impede linear growth, however, recent preclinical research has shown that they also reduce appendicular bone mineral content (BMC) and bone quality in young rats. This is mediated by an increase in osteoclast differentiation and activity, promoting bone resorption. In children and adolescents, the use of psychostimulants has also been associated with clinically significant lower dual-energy x-ray absorptiometry (DXA)-based BMC and areal bone mineral density (aBMD) at the lumbar spine (LS) and hip, in a dose- dependent manner. In addition, our group has found that boys chronically-treated with psychostimulants may have lower LS aBMD velocity Z-scores compared to those not taking psychostimulants. Given that bone mass accrued by young adulthood may determine fracture risk later in life, this application seeks to examine the skeletal effects of psychostimulants in children and adolescents and examine whether sex and pubertal development are significant moderators. Specifically, we propose to enroll otherwise medically healthy 7 to 16 year-olds within one month of starting psychostimulants and unmedicated. In this observational study, we will monitor skeletal outcomes over a one-year period, with repeated DXA and high- resolution pQCT (HRpQCT) scans, along with a thorough assessment of psychopathology and of factors known to affect bone mineral accrual. This design will allow us to prospectively asses the effects of psychostimulants on bone mass accrual and bone microarchitecture in children and adolescents (Aim 1). Given that peak bone accrual velocity in boys is nearly double that in girls and that that bone mass increases exponentially during puberty, we also seek to evaluate whether sex and stages of sexual maturity moderate this effect (Aim 2). Secondary analyses will examine the impact of these medications on additional DXA- and HRpQCT-based outcomes. This study will be the first to prospectively examine whether psychostimulants impair bone mineral accrual during purberty, increasing one's risk for low bone mass later in life. This information is key to designing appropriate interventions to mitigate this risk and to helping clinicians and families make informed decisions about treatment options most suitable for the patient's needs.